The present invention, in some embodiments thereof, relates to pharmacology, and more particularly, but not exclusively, to a novel acid addition salt of a nortriptyline-GABA conjugate, a novel crystalline form of the acid addition salt, to processes of preparing the same and to uses thereof.
Psychotropic drugs are pharmacological agents that act mainly in the central nervous system (CNS) by modulating neuronal signals transduction. Psychotropic drugs are therefore known, and are referred to herein, as pharmacological agents that exert an activity in the CNS to thereby treat various CNS associated impairments, and include, for example, anti-psychotic drugs, anti-depressants, anti-convulsants, anxiolytics, inhibitors of brain-derived enzymes and the like.
The administration of psychotropic drugs is typically associated with adverse side effects, such as seizures, headaches, fatigue, hyperactivity, dizziness, and many more, which severely limit their use. A comprehensive list of such side effects can be found, for example, in “The Merck Manual of Medical Information” (Merck & Co. Inc.).
The prior art teaches the use of GABA agonists (including GABA itself) as potential agents for reducing neuroleptic-induced side effects.
A series of conjugates of psychotropic drugs and organic acids and their use in the treatment of psychotropic and/or proliferative disorders and diseases and for chemosensitization are described in detail in International Patent Applications published as WO 03/026563 and WO 2005/092392 and in U.S. patent application having Publication No. 20040242570, which are all incorporated by reference as if fully set forth herein.
Acid addition salts of such conjugates in which the organic acid has a free amino group (such as in GABA and other GABA agonists) have been disclosed in WO 2006/000666.
A nortriptyline-GABA conjugate (nortriptyline-4-aminobutyrate; BL-1021) has been described in, for example, U.S. Pat. No. 7,619,006 and was further reported to have a beneficial therapeutic effect in the treatment of pain in, for example, WO 2008/010223, which is incorporated by reference as if fully set forth herein.
Crystalline forms, that include polymorphs and pseudopolymorphs, are distinct solids sharing the same structural formula, yet having different physical properties due to different conformations and/or orientations of the molecule in the unit cell of the crystal. The physical characteristics, such as solubility and stability, of different crystalline forms are often different and are thus relevant in the field of pharmacology.
For a general review of crystalline forms (i.e. polymorphs and pseudopolymorphs) and the pharmaceutical applications of crystalline forms see Wall Pharm. Manuf. 1986, 3, 33; Haleblian et al. J. Pharm. Sci. 1969, 58, 911; and Haleblian J. Pharm. Sci., 1975, 64, 1269.